The goal of my research is to identify pathophysiological mechanisms and risk factors of Sudden Unexpected Death in Epilepsy (SUDEP) using transgenic mouse models. It is estimated that SUDEP accounts for up to 17% of all deaths in patients with epilepsy, making it the most common cause of premature mortality in epilepsy. Although the exact mechanism of death in SUDEP remains poorly defined, the MORTality in Epilepsy Monitoring Units Study (MORTEMUS) reported 10 cases of SUDEP where cardiorespiratory dysfunction occurred following a generalized tonic-clonic seizure, which led to central apnea followed by cardiac arrest. Serotonin (5-hydroxytryptamine; 5-HT), an important modulatory neurotransmitter in the brain, has a well- characterized role in the control of breathing and defects in the 5-HT system have been linked to both respiratory dysfunction and SUDEP. For example, mice lacking the 5-HT2C receptor have spontaneous and audiogenic seizures that lead to premature death. Although the cause of death has not be quantitatively studied, anecdotal observations report death results from respiratory arrest. The epileptic phenotype of this strain has been poorly defined and the cause of seizures and premature death remains unclear. 5-HT2C receptors are distributed throughout the brain and a majority of the cells that express this receptor are GABAergic neurons. GABA is the predominant inhibitory neurotransmitter in the brain and disruption of GABAergic signaling is strongly linked to hyperexcitability and seizures. In addition, GABA has an important role in both breathing and cardiovascular control. The Noebels laboratory has previously demonstrated that SUDEP mouse models are at higher risk for brainstem spreading depression, which mediates cardiorespiratory arrest and death. Therefore, I hypothesize that the loss of 5-HT2C receptors causes increased excitability via decreased GABAergic signaling in the brain and an increased risk for brainstem spreading depression. This proposal aims to study the role of 5-HT2C receptor signaling in GABAergic neurons and how the loss of 5-HT2C receptors leads to seizures and cardiorespiratory dysfunction. To achieve these goals, we propose the following research aims: 1) Determine the progression of epilepsy and cause of death in loxTB 5-HT2C mice, and 2) Define the role of 5-HT2C receptor signaling in GABAergic interneurons in CNS excitability and brainstem cardiorespiratory control. The first aim will investigate the cause of death in loxTB 5-HT2C mice and determine whether they have cardiorespiratory abnormalities at baseline and between seizures. The second aim will investigate whether loxTB 5-HT2C mice are at a higher risk for brainstem spreading depression and if 5-HT2C signaling in GABAergic neurons is sufficient to prevent seizures, cardiorespiratory dysfunction, and death in this transgenic line. The experiments proposed in this application will elucidate the role of 5-HT2C signaling in GABAergic neurons in neuron excitability and cardiorespiratory control.